Nanomedicine-boosting icaritin-based immunotherapy of advanced hepatocellular carcinoma

Traditional treatments for advanced hepatocellular carcinoma(HCC),such as surgical resection,transplantation,radiofrequency ablation,and chemotherapy are unsatisfactory,and therefore the exploration of powerful therapeutic strategies is urgently needed.Immunotherapy has emerged as a promising strategy for advanced HCC treatment due to its minimal side effects and long-lasting therapeutic memory effects.Recent studies have demonstrated that icaritin could serve as an immunomodulator for effective immunotherapy of advanced HCC.Encouragingly,in 2022,icaritin soft capsules were approved by the National Medical Products Administration(NMPA)of China for the immunotherapy of advanced HCC.However,the therapeutic efficacy of icaritin in clinical practice is impaired by its poor bioavailability and unfavorable in vivo delivery efficiency.Recently,functionalized drug delivery systems including stimuli-responsive nanocarriers,cell membrane-coated nanocarriers,and living cell-nanocarrier systems have been designed to overcome the shortcomings of drugs,including the low bioavailability and limited delivery efficiency as well as side effects.Taken together,the development of icaritin-based nanomedicines is expected to further improve the immunotherapy of advanced HCC.Herein,we compared the different preparation methods for icaritin,interpreted the HCC immune microenvironment and the mechanisms underlying icaritin for treatment of advanced HCC,and discussed both the design of icaritin-based nanomedicines with high icaritin loading and the latest progress in icaritinbased nanomedicines for advanced HCC immunotherapy.Finally,the prospects to promote further clinical translation of icaritin-based nanomedicines for the immunotherapy of advanced HCC were proposed.

Nanomedicine-based multimodal therapies:Recent progress and perspectives in colon cancer

Colon cancer has attracted much attention due to its annually increasing incidence.Conventional chemotherapeutic drugs are unsatisfactory in clinical application because of their lack of targeting and severe toxic side effects.In the past decade,nanomedicines with multimodal therapeutic strategies have shown potential for colon cancer because of their enhanced permeability and retention,high accumulation at tumor sites,co-loading with different drugs,and combination of various therapies.This review summarizes the advances in research on various nanomedicine-based therapeutic strategies including chemotherapy,radiotherapy,phototherapy(photothermal therapy and photodynamic therapy),chemodynamic therapy,gas therapy,and immunotherapy.Additionally,the therapeutic mechanisms,limitations,improvements,and future of the above therapies are discussed.

Importance of Standardizing Analytical Characterization Methodology for Improved Reliability of the Nanomedicine Literature

Understanding the interaction between biological structures and nanoscale technologies,dubbed the nano-bio interface,is required for successful development of safe and efficient nanomedicine products.The lack of a universal reporting system and decentralized methodologies for nanomaterial characterization have resulted in a low degree of reliability and reproducibility in the nanomedicine literature.As such,there is a strong need to establish a characterization system to support the reproducibility of nanoscience data particularly for studies seeking clinical translation.Here,we discuss the existing key standards for addressing robust characterization of nanomaterials based on their intended use in medical devices or as pharmaceuticals.We also discuss the challenges surrounding implementation of such standard protocols and their implication for translation of nanotechnology into clinical practice.We,however,emphasize that practical implementation of standard protocols in experimental laboratories requires long-term planning through integration of stakeholders including institutions and funding agencies.

The endocytosis and intracellular fate of nanomedicines: Implication for rational design

Nanomedicines employ multiple endocytic pathways to enter cells.Their following fate is interesting,but it is not sufficient understood currently.This review introduces the endocytic pathways,presents new technologies to confirm the specific endocytic pathways and discusses factors for pathway selection.In addition,some intriguing implication about nanomedicine design based on endocytosis will also be discussed at the end.This review may provide new thoughts for the design of novel multifunctional nanomedicines.

Multimodality imaging in nanomedicine and nanotheranostics

Accurate diagnosis of tumors needs much detailed information. However, available single imaging modality cannot provide complete or comprehensive data. Nanomedicine is the application of nanotechnology to medicine, and multimodality imaging based on nanoparticles has been receiving extensive attention. This new hybrid imaging technology could provide complementary information from different imaging modalities using only a single injection of contrast agent. In this review, we introduce recent developments in multifunctional nanoparticles and their biomedical applications to multimodal imaging and theragnosis as nanomedicine. Most of the reviewed studies are based on the intrinsic properties of nanoparticles and their application in clinical imaging technology. The imaging techniques include positron emission tomography, single-photon emission computed tomography, computerized tomography, magnetic resonance imaging, optical imaging, and ultrasound imaging.

Overcoming the cellular barriers and beyond: Recent progress on cell penetrating peptide modified nanomedicine in combating physiological and pathological barriers

The complex physiological and pathological conditions form barriers against efficient drug delivery.Cell penetrating peptides(CPPs),a class of short peptides which translocate drugs across cell membranes with various mechanisms,provide feasible solutions for efficient delivery of biologically active agents to circumvent biological barriers.After years of development,the function of CPPs is beyond cell penetrating.Multifunctional CPPs with bioactivity or active targeting capacity have been designed and successfully utilized in delivery of various cargoes against tumor,myocardial ischemia,ocular posterior segment disorders,etc.In this review,we summarize recent progress in CPP-functionalized nano-drug delivery systems to overcome the physiological and pathological barriers for the applications in cardiology,ophtalmology,mucus,neurology and cancer,etc.We also highlight the prospect of clinical translation of CPP-functionalized drug delivery systems in these areas.

Nanomedicine potentiates mild photothermal therapy for tumor ablation

The booming photothermal therapy(PTT)has achieved great progress in non-invasive oncotherapy,and paves a novel way for clinical oncotherapy.Of note,mild temperature PTT(mPTT)of 42–45°C could avoid treatment bottleneck of the traditional PTT,including nonspecific injury to normal tissues,vasculature and host antitumor immunity.However,cancer cells can resist mPTT via heat shock response and autophagy,thus leading to insufficient mPTT monotherapy to ablate tumor.To overcome the deficient antitumor efficacy caused by thermo-resistance of cancer cells and mono mPTT,synergistic therapies towards cancer cells have been conducted with mPTT.This review summarizes the recent advances in nanomedicine-potentiated mPTT for cancer treatment,including strategies for enhanced single-mode mPTT and mPTT plus synergistic therapies.Moreover,challenges and prospects for clinical translation of nanomedicine-potentiated mPTT are discussed.

The role of transporters in cancer redox homeostasis and cross-talk with nanomedicines

Tumor cell usually exhibits high levels of reactive oxygen species and adaptive antioxidant system due to the metabolic,genetic,and microenvironment-associated alterations.The altered redox homeostasis can promote tumor progression,development,and treatment resistance.Several membrane transporters are involved in the resetting redox homeostasis and play important roles in tumor progression.Therefore,targeting the involved transporters to disrupt the altered redox balance emerges as a viable strategy for cancer therapy.In addition,nanomedicines have drawn much attention in the past decades.Using nanomedicines to target or reset the redox homeostasis alone or combined with other therapies has brought convincing data in cancer treatment.In this review,we will introduce the altered redox balance in cancer metabolism and involved transporters,and highlight the recent advancements of redox-modulating nanomedicines for cancer treatment.

γ⁃Fe2O3@carboxymethyl Cellulose as Potential Oral Nanomedicine for Iron Deficiency Anemia Treatment on Rats

Oral iron supplements such as ferrous iron salts are major treatment agents for iron deficiency anemia(IDA)due to the convenience of large dose administration and good patient compliance.However,the gastrointestinal adverse impact caused by Fe2+stimulus and low bioavailability severely impedes its therapeutic effects.In recent years,it has been found that nano iron⁃based nanoparticles with high surface⁃to⁃volume ratio and low iron ion leakage can alleviate the toxic effect and improve the gastrointestinal absorbance.For further clinical development,nano materials need to meet the pharmaceutical quality demand.Carboxymethyl cellulose(CMC)is a significant pharmaceutical ingredient applied in approved drug formulations,and polyglucosorbitol carboxymethylether(PSC)has been utilized in iron⁃based nanomedicine ferumoxytol synthesis,both of which can be firmly anchored on iron oxide by carboxyl chelation.In this work,iron oxide nanoparticles(NPs)modified with CMC were designed and synthesized,and the structure composition and physicochemical properties were distinctly characterized.Oral supplement effects on rat IDA were investigated and compared with other recently reported iron supplements including NPs modified with PSC.Results show that the oral nano iron supplement achieved the recovery of hemoglobin and serum iron level in only two weeks with high safety.The nano iron oxide modified with pharmaceutical excipients provides new potential approach for oral iron supplement available in clinics.

Mechanotransduction,nanotechnology,and nanomedicine

Mechanotransduction,a conversion of mechanical forces into biochemical signals,is essential for human development and physiology.It is observable at all levels ranging from the whole body,organs,tissues,organelles down to molecules.Dysregulation results in various diseases such as muscular dystrophies,hypertension-induced vascular and cardiac hypertrophy,altered bone repair and cell deaths.Since mechanotransduction occurs at nanoscale,nanosciences and applied nanotechnology are powerful for studying molecular mechanisms and pathways of mechanotransduction.Atomic force microscopy,magnetic and optical tweezers are commonly used for force measurement and manipulation at the single molecular level.Force is also used to control cells,topographically and mechanically by specific types of nano materials for tissue engineering.Mechanotransduction research will become increasingly important as a sub-discipline under nanomedicine.Here we review nanotechnology approaches using force measurements and manipulations at the molecular and cellular levels during mechanotransduction,which has been increasingly play important role in the advancement of nanomedicine.

Nanomedicine strategies for sustained,controlled,and targeted treatment of cancer stem cells of the digestive system

Cancer stem cells(CSCs) constitute a small proportion of the cancer cells that have self-renewal capacity and tumor-initiating ability.They have been identified in a variety of tumors,including tumors of the digestive system.CSCs exhibit some unique characteristics,which are responsible for cancer metastasis and recurrence.Consequently,the development of effective therapeutic strategies against CSCs plays a key role in increasing the efficacy of cancer therapy.Several potential approaches to target CSCs of the digestive system have been explored,including targeting CSC surface markers and signaling pathways,inducing the differentiation of CSCs,altering the tumor microenvironment or niche,and inhibiting ATP-driven efflux transporters.However,conventional therapies may not successfully eradicate CSCs owing to various problems,including poor solubility,stability,rapid clearance,poor cellular uptake,and unacceptable cytotoxicity.Nanomedicine strategies,which include drug,gene,targeted,and combinational delivery,could solve these problems and significantly improve the therapeutic index.This review briefly summarizes the ongoing development of strategies and nanomedicine-based therapies against CSCs of the digestive system.

Recent Advances of D-α-tocopherol Polyethylene Glycol 1000 Succinate Based Stimuli-responsive Nanomedicine for Cancer Treatment

D-a-tocopherol polyethylene glycol 1000 succinate(TPGS)is a pharmaceutical excipient approved by Chinese NMPA and FDA of USA.It's widely applied as a multifunctional drug carrier for nanomedicine.The advantages of TPGS include P-glycoprotein(P-gp)inhibition,penetration promotion,apoptosis induction via mitochondrial-associated apoptotic pathways,multidrug resistant(MDR)reversion,metastasis inhibition and so on.TPGS-based drug delivery systems which are responding to extermal stimulus can combine the inhibitory functions of TPGS towards P-gp with the environmentally responsive controlled release property and thus exerts a synergistic anti-cancer effect,through increased intracellular drug concentration in tumors cells and well-controlled drug release behavior.In this review,TPGS-based nano-sized delivery systems responsive to different stimuli were summarized and discussed,including pH-responsive,redox-responsive and multi-responsive systems in various formulations.The achievements,mechanisms and diffcrent characteristics of TPGS-bascd stimuli-responsive drug-delivery systems in tumor therapy were also outlined.

Nanotechnology and Nanomedicine: A Promising Avenue for Lung Cancer Diagnosis and Therapy

Lung cancer is a leading cause of cancer-related death worldwide,with a very poor overall five-year survival rate.The intrinsic limitations associated with the conventional diagnosis and therapeutic strategies used for lung cancer have motivated the development of nanotechnology and nanomedicine approaches,in order to improve early diagnosis rate and develop more effective and safer therapeutic options for lung cancer.Cancer nanomedicines aim to individualize drug delivery,diagnosis,and therapy by tailoring them to each patient’s unique physiology and pathological features—on both the genomic and proteomic levels—and have attracted widespread attention in this field.Despite the successful application of nanomedicine techniques in lung cancer research,the clinical translation of nanomedicine approaches remains challenging due to the limited understanding of the interactions that occur between nanotechnology and biology,and the challenges posed by the toxicology,pharmacology,immunology,and largescale manufacturing of nanoparticles.In this review,we highlight the progress and opportunities associated with nanomedicine use for lung cancer treatment and discuss the prospects of this field,together with the challenges associated with clinical translation.

Nanomedicine in the application of uveal melanoma

Rapid advances in nanomedicine have significantly changed many aspects of nanoparticle application to the eye including areas of diagnosis, imaging and more importantly drug delivery. The nanoparticle-based drug delivery systems has provided a solution to various drug solubility-related problems in ophthalmology treatment.Nanostructured compounds could be used to achieve local ocular delivery with minimal unwanted systematic side effects produced by taking advantage of the phagocyte system. In addition, the in vivo control release by nanomaterials encapsulated drugs provides prolong exposure of the compound in the body. Furthermore,certain nanoparticles can overcome important body barriers including the blood-retinal barrier as well as the corneal-retinal barrier of the eye for effective delivery of the drug. In summary, the nanotechnology based drug delivery system may serve as an important tool for uveal melanoma treatment.

Nanomedicine:diagnosis to therapy

It can be said that "small technology" becomes a very useful technology and is replacing the classical technology. Nanotechnology is an applied technology relating to management,construction,synthesis of devices in atomic or molecular level that poses the size between 1 and 100 nanometers.In this short article,the author will summarize important advent in nanodiagnosis and nanotherapy then further extrapolate this for the tropical medicine aspect.

Nanomedicine approaches for treatment of hematologic and oncologic malignancies

Cancer is a leading cause of death worldwide.Nowadays,the therapies are inadequate and spur demand for improved technologies.Rapid growth in nanotechnology and novel nanomedicine products represents an opportunity to achieve sophisticated targeting strategies and multi-functionality.Nanomedicine is increasingly used to develop new cancer diagnosis and treatment methods since this technology can modulate the biodistribution and the target site accumulation of chemotherapeutic drugs,thereby reducing their toxicity.Cancer nanotechnology and cancer immunotherapy are two parallel themes that have emerged over the last few decades while searching for a cure for cancer.Immunotherapy is revolutionizing cancer treatment,as it can achieve unprecedented responses in advanced-stage patients,including complete cures and long-term survival.A deeper understanding of the human immune system allows the establishment of combination regimens in which immunotherapy is combined with other treatment modalities(as in the case of the nanodrug Ferumoxytol).Furthermore,the combination of gene therapy approaches with nanotechnology that aims to silence or express cancer-relevant genes via one-time treatment is gradually progressing from bench to bedside.The most common example includes lipidbased nanoparticles that target VEGF-Αand KRAS pathways.This review focuses on nanoparticle-based platforms utilized in recent advances aiming to increase the efficacy of currently available cancer therapies.The insights provided and the evidence obtained in this paper indicate a bright future ahead for immunooncology applications of engineering nanomedicines.

Nanomedicine-based approaches for delivery of herbal compounds

Herbal compounds have enormous potential to enhance the efficacy of current cancer treatments.Several herbal compounds have been reported to enhance the effect of chemotherapy,hormonal therapy and gene therapy on tumor cells.Compared to synthetic formulations,natural products are considered safer and do not have toxic effects at therapeutic doses,thus increasing demand for them.These compounds can significantly effect on signal transduction pathways,reduce side effects,and even inhibit the efflux of anticancer drugs.This review will explain factors influencing herbal nanomedicines,targeting of nanomedicines,nanocarriers used for delivery,herbal nanomedicines in cancer,phytochemical based combinatorial nanomedicines,and challenges to the nanocarriers based cancer therapy.

Nanomedicine: Tiny Particles and Machines, from Diagnosis to Treatment of Cardiovascular Disease, Provides Huge Achievements

Cardiovascular disease is one of many reverberating ailments that affect and kill hundreds of thousands of people around the world. To date treatments that offer improvement in the health condition of diseased people include the most promising nanomedicine although it is in its infancy, yet attaining attention from researchers of top notch day by day. In this current review importance is given on the application of nanomedicine in the diagnosis as well as treatment of cardiovascular disease.

In Vivo Animal Model Evaluation of a Powerful Oral Nanomedicine for Treating Breast Cancer in BALB/c Mice Using 4T1 Cell Lines without Chemotherapy

Nanopharmaceuticals containing quantum dot nanoparticles (Q-Dot NPs) for treating serious cancers such as breast cancer have made fantastic proposals. In this study, ZnO quantum dot NPs are formulated via ZnO@PVP nanopolymer as co-assistants coordinating with efficacious suitable wetting agents, PEG-binding compound, and W/O emulsifier for producing eco-friendly water-based nanodrug. Several characterization techniques containing SEM, TEM, FTIR, photoluminescence, zeta potential, and UV-Vis absorption were employed for ZnO Q-Dot NPs in nanodrug. This work aims to investigate the anti-tumor effects of such nanomedicine on the 4T1 breast cancer cell line in BALB/c mice, being elaborated through intraperitoneal, injection (IVP) and oral therapy. The impressive findings showed that ZnO nanodrug caused changes in blood factors, having the most effectiveness at 40 μg/ml concentration after two weeks of oral treatments. The significant increase in white blood cells (WBC) neutrophils and meaningful decreases in lymphocytes and especially cholesterol were powerful simultaneous impacts, successfully treating malignant breast cancer masses. In this significant animal model research for breast cancer, the sick mice recovered entirely and even had a safe space to mate. Histopathological results showed no evidence of breast tumor formation or metastasis in the group treated with nanodrug and their children. This nanomedicine has a therapeutic effect, and is ready to be applied for treating volunteer breast cancer patients. However, its prevention (inhibitory) effect can also be analyzed and added to current data in future studies.

Nanomedicine has opened new avenues for cancer diagnosis and therapy

A crucial feature of nanoparticles,such as liposomes,magnetic nanoparticles,quantum dots,metallic nanoparticles,silica nanoparticles,polymersomes and dendrimers etc.,is their higher accumulation in the tumor than in normal tissues1-3.Various nanoparticles have been intensively used as vehicles to deliver